The cannabinoid receptors CB1 and CB2 are molecular targets for Δ9-tetrahydrocannabinol, the psychoactive component of marijuana. CB1 which is expressed mainly in the brain, but also in the lungs, liver and kidneys. CB2 which is mainly expressed in the immune system and in hematopoietic cells. Two endogenous ligands, or “endocannabinoids,” have also been identified, the arachidonate-based lipids anandamide (N-arachidonoyl ethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). The endocannabinoid system regulates a range of physiological processes, including appetite, pain sensation, inflammation, and memory, and is the current focus of considerable pharmaceutical interest to treat disorders such as obesity, chronic pain, anxiety, and depression.
Endocannabinoid signaling is tightly controlled by enzymatic hydrolysis. Hydrolysis of 2-AG or AEA leads to production of arachidonic acid (AA). The principal AEA-hydrolyzing enzyme is fatty acid amide hydrolase (FAAH). Genetic or pharmacological disruption of FAAH causes significant elevations in AEA levels throughout the nervous system and periphery, resulting in multiple CB1- and/or CB2-dependent behavioral effects, including reduction in pain sensation, inflammation, anxiety, and depression. Interestingly, several of the other well-known behavioral effects of direct CB1 agonists, such as hypothermia and movement disorders, are not observed in FAAH-disrupted animals (Goparaju et al., FEBS Lett. 422:69-73, 1998; and Kathuria et al., Nat Med 9:76-81, 2003). These animals also possess wild-type levels of 2-AG17, which suggests that additional CB1-regulated behavioral processes may be mediated by 2-AG in vivo. Several lines of evidence suggest that monoacylglycerol lipase (MAGL) is a primary enzyme responsible for hydrolyzing 2-AG in the nervous system. See, e.g., Dinh et al., Proc. Natl. Acad. Sci. USA 99:10819-24, 2002; Dinh et al., Mol. Pharmacol. 66:1260-4, 2004; Blankman et al., Chem. Biol. 14:1347-56, 2007; and Nomura et al., Nat. Chem. Biol. 4:373-8, 2008. However, none of these previous studies have specifically examined the role that MAGL plays in hydrolyzing 2-AG in vivo. While several MAGL inhibitors have been described in the art (Hohmann et al., Nature 435:1108-12, 2005; Varvel et al., J. Pharmacol. Exp. Ther. 301:915-24, 2002; and Saario et al., Chem. Biol. 12:649-56, 2005), none of them show the level of potency and specificity required for general use as in vivo pharmacological tools.
Tumors and cancers are common diseases or conditions that threaten many people's life and health. Uninhibited growth of aggressive tumor cells often results in the formation of malignant tumors (cancer). There are still no effective medicines or treatments which can radically cure cancers. At present, main methods used in the treatment of tumor are operation, radiotherapy, chemotherapy, biologic therapy, and others such as endocrine treatment, Chinese traditional therapy, thermotherapy, radiofrequency ablation therapy and so on. However, most available treatments can only relieve the patients' symptom and physical sign but can not cure the disease, and each of the treatments usually has its disadvantages including side effects.
There is a need in the art for compounds that can potently and selectively inhibit MAGL in vivo, and for novel means for treating conditions or disorders that are associated with or linked to endocannabinoid signaling activities. There us also a need for alternative and more effective means for inhibiting tumor growth and for treating cancers. The present invention addresses these and other unfulfilled needs in the art.